Nitric oxide (NO) is a major signaling molecule in the mammalian immune, cardiovascular and nervous systems.18,26,37,56,57,109 NO produced at one site can have an effect on tissues at a distance.24,70 NO is produced from L-arginine by the enzyme, nitric oxide synthase (NOS).55,57 NOS occurs in three forms: endothelial (e), neuronal (n), and inducible (i) NOS. The first two forms are constitutively expressed and Ca2+ dependent. Inducible (i) NOS is Ca2+ independent. The three forms of NOS are encoded for on three distinct genes on chromosomes, 7, 12, and 17, respectively.18,26,37,54 In general, n- and e-NOS depend on intracellular calcium transients and release NO in the nM range, whereas iNOS, following an induction/latency period, can release NO in the μM range for extended periods of time.18,26,28,37,56,57,70,105,109 The presence of constitutive and inducible forms of NOS suggest that they may have distinct functions.
c- and i- NOS can be distinguished on the basis of the length of time necessary to see an increase in levels of NO and the length of time these elevated levels can be maintained. NO derived from cNOS may occur in two functional forms: the first is always present at low “tonal” or “basal” levels; this basal level can be slightly increased for a short time in response to certain signals, e.g., acetylcholine (ACH).56 This brief enhanced release of cNOS derived NO can have profound physiological actions, which are evident long after NO has returned to its basal level, for a longer period of time.50 For example, endothelial cells briefly exposed to morphine and eNOS change their shape from elongated to round, a process that takes several hours.50 
iNOS is induced by various signal molecules, e.g., proinflammatory cytokines.57,73,105 The induction of i-NOS is usually seen after a 3-4 hour delay; iNOS is capable of producing NO for 24-48 hours.73,105 These data suggest that NO is always present and that the levels of NO can be regulated either rapidly or slowly depending on the organism's needs. The presence of different regulatory processes implies that NO has different functions, and/or that the levels of NO must be progressively increased in order for it to exert its function.
NO functions as a vascular, immune and neural signal molecule and also has general antibacterial, antiviral actions and the ability to down-regulated proinflammatory events.38-39,41-42,60,90,105-106 In the vascular and immune system, one of the key stages in the immune response is the recruitment and activation of leukocytes by the endothelium. Leukocyte activation by the endothelium occurs in stages. The initial step is the attraction of the leukocytes to the endothelium. This is followed by increased leukocyte adhesion and change in shape and finally migration across the endothelium.90 These cellular changes are accompanied by scheduled changes in synthesis of molecules that regulate cell-matrix interactions.3,46,52,87 
Normally, non-activated leukocytes roll along the endothelium. The interaction between the two cell types is loose and reversible and mediated by a family of adhesion molecules known as selectins. Activation of leukocytes occurs in response to the release of several chemoattractants including leukotriene B4 and interleukin 8 (IL-8). In the presence of these agents, immunocytes cease to roll, becoming “activated”: they start to flatten and adhere with greater strength to the endothelial lining. Activation is mediated by a family of adhesion molecules call the integrins, such as ICAM-1 and VCAM-1. Adherent immunocytes are able to undergo transendothelial migration in the presence of PECAM-1.3,46,52,87 This immunocyte-endothelial interaction is down-regulated by NO. NO inhibits platelet and neutrophil aggregation and can diminish the adherence and level of activation of leukocytes and endothelial cells.41,1,50, 109 NOS inhibitors increase platelet adhesion and enhance leukocyte adhesion.72,82 NO plays a similar role involving the microglia cells of the nervous system's immune response.83,84 
The central nervous system (CNS) is unique in that it uses all three isoforms of NOS to produce NO. The constitutive isoforms e- and n- NOS are found in the normal CNS; however, iNOS is not expressed in the healthy CNS.20 Pathological states, e.g., trama, cerebral ischemia and neuronal diseases, increase the levels of e- and nNOS and induce iNOS activity.21 cNOS derived NO has the ability to down-regulate proinflammatory events via inhibition of NF-κB activation of proinflammatory cytokines.
NO upregulates several enzymes involved in immunoregulation, including neutral endopeptidese 24.11 (CALLA, acute lymphoblastic leukemic antigen, enkephalinase) or CD10.76 Thus, cNOS derived No stimulates enzymes that process protein gene products, implying a link between signaling processes involving NO and naturally occurring antibacterial peptides. No controls and regulates enzymes that are responsible for liberating these crucial molecules that have a proactive protective function.101 
Evidence has also been provided that NO plays a role in neurotransmitter release.102 Morphine and cNOS derived NO release growth hormone and ACTH from rat brain fragments; these neuropeptides are involved in the stress response. Thus, NO is involved in vasodilation, antibacterial and antiviral responses, signal molecule release and inhibition of immunocyte adherence to the endothelium.
There appears to be a tonal or basal level of NO that is physiologically significant. Endothelia from non-insulin dependent diabetics do not exhibit a tonal level of NO117 and in these individuals vascular disease causes disability and eventual death.14 A number of researchers have attributed vascular disease in part to alterations associated with eNOS-derived NO and some have speculated this may be due to enhanced free radical generation.59 Decreases in basal NO levels may also contribute to enhanced platelet function and various neuropathies.32,68 
Thus, it appears that tonal or basal NO levels are important in limiting the degree of excitation of nervous, immune and vascular tissues. This tonal NO may manifest itself via effects on adhesion-mediated processes via NF-κB. Estrogen may exert it beneficial vascular protective actions via these processes as well, since it also releases cNOS derived NO.70,99 Strengthening this hypothesis in the finding of the cannabinoid CB1 receptor type on mammalian endothelial cells118,119 and the finding of a mu opiate receptor on human vascular endothelial cells. (Three general classes of cell surface opioid receptors (kappa, delta and mu) have been described. Receptors exhibiting high binding specificity for morphine have been designated mu opioid receptors.) Detailed analysis has revealed the existence of multiple mu opioid receptor subtypes. Isolated nucleic acid sequences encoding various mu receptors and polypeptides comprising mu receptors (and referred to here as “mu3 opioid receptor(s)”) are disclosed in detail in PCT Patent Publication WO 99/24471, published 20 May 1999. See also, Molecular Identification and Functional Expression of μ3, a Novel Alternatively Spliced Variant of the Human μ Opiate Receptor Gene.
Consequently, promoting NO generation at normal or slightly enhanced levels may have significant health value. While the health promoting effects of many plants are well known, how and why this occurs at a molecular level is less understood. See Stefano and Miller, Communication between animal cells and the plant foods they ingest: Phyto-zooidal dependencies and signalling (Review), Intl J Mol Medicine 10: 413-21 (2002) incorporated by reference herein.